EP1616861A2 - A process for the preparation of keto compounds - Google Patents
A process for the preparation of keto compounds Download PDFInfo
- Publication number
- EP1616861A2 EP1616861A2 EP05011646A EP05011646A EP1616861A2 EP 1616861 A2 EP1616861 A2 EP 1616861A2 EP 05011646 A EP05011646 A EP 05011646A EP 05011646 A EP05011646 A EP 05011646A EP 1616861 A2 EP1616861 A2 EP 1616861A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- formula
- compound
- ranges
- sulfuric acid
- alkanol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- LNQJRLLXDQRHIW-UHFFFAOYSA-N CC(C)(C(O)=O)c(cc1)ccc1C#CCCN(CC1)CCC1C(c1ccccc1)(c1ccccc1)O Chemical compound CC(C)(C(O)=O)c(cc1)ccc1C#CCCN(CC1)CCC1C(c1ccccc1)(c1ccccc1)O LNQJRLLXDQRHIW-UHFFFAOYSA-N 0.000 description 1
- NGAKDIWPTMPPFP-UHFFFAOYSA-N CC(C)(C(O)=O)c(cc1)ccc1C(CCCN(CC1)CCC1C(c1ccccc1)(c1ccccc1)O)=O Chemical compound CC(C)(C(O)=O)c(cc1)ccc1C(CCCN(CC1)CCC1C(c1ccccc1)(c1ccccc1)O)=O NGAKDIWPTMPPFP-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
- C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/08—Bronchodilators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- the alkyne of formula ( II ) is reacted in the form of a solution in a C 1 -C 4 alkanol, as defined above, in a concentration approx. from 10 to 30%, preferably from 15 to 25% weight/volume.
- the reaction is carried out contacting the alkanol solution of the alkyne of formula ( II ) with the sulfuric acid aqueous solution in molar amounts of sulfuric acid to alkyne of formula ( II ) ranging approx. from 0.8 to 1.2, preferably from 0.9 to 1.1.
- the resulting solution is added with HgO in molar amounts to the alkyne of formula ( II ) ranging approx. from 0.01 to 0.05, preferably from 0.02 to 0.04.
- the reaction is carried out at a temperature ranging approx. from 20 to 60°C, preferably from 30 to 50°C.
Abstract
Description
- The present invention relates to a novel process for the preparation of 4-[1-oxo-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl]-α,α-dimethylbenzeneacetic acid and its use in the preparation of fexofenadine.
- A number of processes for the preparation of fexofenadine are known, for example those disclosed in WO 93/21156, WO 97/22344 and WO 97/23213, characterized by a high number of steps. None of the known processes involves a convergent approach, but the construction of the molecule through stepwise introduction of the different functionalities starting from α,α-dimethylbenzeneacetic acid. An alternative route is described by Kawai S. et al. in J. Org. Chem. 1994, 59, 2620-2622, but it has some disadvantages which prevent its industrial application. A key step in said synthetic route is, in fact, the hydration of the alkyne bond in the carboxymethyl ester of formula (A) to give the respective keto derivative of formula (B).
- This is however accompanied by formation of by-products, which are difficult to remove from the final product. The paper by Kawai S. et al. describes in fact the subsequent purification of the ketone of formula (B) by silica gel chromatography. It is well-known that this technique is hardly suitable for the production of large amounts of the product, so that this process is not industrially applicable. The problem of the formation of by-products was solved by EP 1260505, in which the hydration is carried out using a catalyst based on platinum, palladium or ruthenium, optionally in the presence of ligands. The very high cost of these catalysts, however, negatively affects the final costs. Therefore, there still is the problem of hydrating the alkyne bond to obtain the corresponding keto compound, avoiding the formation of hardly removable by-products as well as the increase in industrial production costs.
- It has now surprisingly been found that the reaction between the alkyne of formula (A), in the form of the free carboxylic acid, and a solution of HgO in H2SO4 provides the respective keto derivative in industrial yields, without need for expensive catalysts as well as complex, time-consuming purification operations.
-
- A C1-C4 alkanol, in which the alkyl moiety can be straight or branched, is preferably methanol or ethanol, in particular methanol.
- The alkyne of formula (II) is reacted in the form of a solution in a C1-C4 alkanol, as defined above, in a concentration approx. from 10 to 30%, preferably from 15 to 25% weight/volume.
- The sulfuric acid aqueous solution is typically a solution approx. from 30 to 50%, preferably from 35 to 45% weight/volume.
- The reaction is carried out contacting the alkanol solution of the alkyne of formula (II) with the sulfuric acid aqueous solution in molar amounts of sulfuric acid to alkyne of formula (II) ranging approx. from 0.8 to 1.2, preferably from 0.9 to 1.1. The resulting solution is added with HgO in molar amounts to the alkyne of formula (II) ranging approx. from 0.01 to 0.05, preferably from 0.02 to 0.04. The reaction is carried out at a temperature ranging approx. from 20 to 60°C, preferably from 30 to 50°C.
- After completion of the reaction, the reaction mixture is alkalinised with a sodium hydroxide methanolic solution, the resulting sodium salt of the ketone of formula (I) is transformed into the corresponding free acid by treatment with a mineral acid, such as hydrochloric, sulfuric or phosphoric acid, or an organic acid, for example acetic, methanesulfonic or oxalic acid.
- The resulting ketone of formula (I): 4-{[4-(4-hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl}-α,α-dimethylbenzeneacetic acid, has crystalline structure having X-ray diffraction spectrum (X-ray powder diffraction, XRPD) substantially as reported in the Figure, the more intense diffraction peaks being observed at 10.05; 12.03; 15.33; 15.78; 17.34; 17.64; 20.13 and 23.67 in 2θ, and this is a further object of the invention. The XRPD spectrum was recorded with an
APD 2000 automatic diffractometer θ/θ for powders and liquids (available from Ital-Structures), under the following operative conditions: CuKα radiation (λ = 1.5418 A), scanning with angular pass of 0.03° for a time of 1 sec". - The comparative data reported in the following table show the advantages provided by the process of the present invention compared with that described by Kawai S. et al.
Table Starting alkyne Starting mols Keto compound Mols of keto compound % Yield Compound (A) 1.18 Compound (B) 0.885 75 Compound (II) 1.18 Compound (I) 1.062* 90* 0.968** 82** (*): values obtained by titration of the final reaction mixture. (**): values concerning the isolated product. - Since the formed by-products are difficult to remove, when the reaction is carried out according to Kawai S. et al., the purification of the ketone of formula (B) is carried out by silica gel chromatography (1:2 → 3:1 ethyl acetate - hexane, then 15:1 CH2-Cl2 - methanol, v/v), as described in the same paper. On the other hand, the keto compound of formula (I), after work up, is separated by simple precipitation. Moreover, the amount of HgO used according to the process of the invention is about 1/10 that used by Kawai S. et al., thereby reducing the environmental impact.
- The keto compound of formula (I) can be subsequently reduced to obtain fexofenadine of formula (III)
by means of known procedures, for example, by a process comprising the reduction with a reducing agent, such as sodium borohydride, potassium borohydride, sodium cyanoborohydride or tetramethylammonium borohydride, in a suitable alkanol, such as methanol, ethanol, isopropanol, n-butanol or mixtures thereof with water, at a temperature ranging from about 0°C to the reflux temperature of the reaction mixture. If desired, fexofenadine can then be converted into a salt, for example the hydrochloride, according to known methods. - Therefore, the present invention also relates to a process for the preparation of fexofenadine, or a pharmaceutically acceptable salt thereof, comprising the reduction of a keto compound of formula (I)
and, if desired, the conversion into a salt thereof, such as the hydrochloride, characterized in that the compound of formula (I) is obtained by reaction of a compound of formula (II)
with a sulfuric acid aqueous solution, in the presence of mercury(II) oxide, in a C1-C4 alkanol, as herein described. - The following example illustrates the invention.
- A four-necked three litres flask, equipped with stirrer, thermometer, condenser and kept under nitrogen, is loaded with 353 g of 4-{[4-(4-hydroxydiphenylmethyl)-1-piperidinyl]-1-butynyl}-α,α-dimethylbenzeneacetic acid and 1790 ml of methanol. A solution of 72 g of 96% w/w sulfuric acid in 185 g of water is prepared in a 500 ml flask and added with 4.1 g of mercury(II) oxide under stirring. The resulting suspension of 4-{[4-(4-hydroxydiphenylmethyl)-1-piperidinyl]-1-butynyl}-α,α-dimethylbenzeneacetic acid in methanol is added with the mercury sulfate aqueous solution prepared above. The resulting solution is heated at about 40°C under stirring, keeping this temperature until completion of the reaction. (The yield being now above 90%). A solution of sodium hydroxide scales (86 g) in 430 ml of methanol is prepared and added with the reaction mixture at room temperature: temperature spontaneously raises, to obtain a suspension. The mixture is refluxed and 66 g of glacial acetic acid are dropped therein. After adding approx. 30% of the acid, crystallization is started with the previously obtained pure keto compound (I), and the addition is completed. After that, the mixture is refluxed for about 15-20 minutes, then cooled in approx. 2 hours at 25-30°. The mixture is left at this temperature for approx. an hour and the solid is filtered and washed with methanol (2x100 ml). The resulting solid is further purified from the inorganic salts by hot trituration in 950 ml of water and filtration at 60-65°C. After washing with 100 ml x 2 of water and washing with 100 ml x 2 of methanol, the product is dried. 281 g of compound (I) in the crystalline form, having an XRPD spectrum substantially as reported in the Figure, are obtained; (purity above 99.5%; yield 82%).
Claims (13)
- A process as claimed in claim 1, wherein the alkanol is methanol or ethanol.
- A process as claimed in claims 1 or 2, wherein the concentration of the compound of formula (II) in the alkanol ranges from 10 to 30% weight/volume.
- A process as claimed in claims 1 or 3, wherein the concentration of the sulfuric acid aqueous solution ranges from 30 to 50% weight/volume.
- A process as claimed in claims 1 or 4, wherein the molar amount of sulfuric acid to compound of formula (II) ranges from 0.8 to 1.2.
- A process as claimed in claim 5, wherein the molar amount of sulfuric acid to compound of formula (II) ranges from 0.9 to 1.1.
- A process as claimed in claims 1 or 6, wherein the molar amount of mercury(II) oxide to compound of formula (II) ranges from 0.01 to 0.05.
- A process as claimed in claim 7, wherein the molar amount of mercury(II) oxide to compound of formula (II) ranges from 0.02 to 0.04.
- 4-{[4-(4-Hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl}-α,α-dimethylbenzeneacetic acid in the crystalline form.
- A process for the preparation of fexofenadine, or a pharmaceutically acceptable salt thereof, comprising the reduction of a keto compound of formula (I)
- A process as claimed in claim 10, wherein the fexofenadine salt is the hydrochloride.
- A crystalline form of the acid of claim 9, having an XRPD spectrum substantially as reported in the Figure.
- A crystalline form as claimed in claim 12, having an XRPD spectrum in which the more intense diffraction peaks are observed at 10.05; 12.03; 15.33; 15.78; 17.34; 17.64; 20.13 and 23. 67 in 20.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
ITMI20041191 ITMI20041191A1 (en) | 2004-06-15 | 2004-06-15 | PROCEDURE FOR THE PREPARATION OF KETONIC COMPOUNDS |
ITMI20041397 ITMI20041397A1 (en) | 2004-07-13 | 2004-07-13 | PROCEDURE FOR THE PREPARATION OF KETONIC COMPOUNDS |
Publications (2)
Publication Number | Publication Date |
---|---|
EP1616861A2 true EP1616861A2 (en) | 2006-01-18 |
EP1616861A3 EP1616861A3 (en) | 2006-02-08 |
Family
ID=35461376
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP05011646A Withdrawn EP1616861A3 (en) | 2004-06-15 | 2005-05-31 | A process for the preparation of keto compounds |
Country Status (4)
Country | Link |
---|---|
US (1) | US20050277775A1 (en) |
EP (1) | EP1616861A3 (en) |
JP (1) | JP2006001931A (en) |
CA (1) | CA2510001A1 (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1992615A1 (en) | 2007-05-16 | 2008-11-19 | Dipharma Francis S.r.l. | A process for the preparation of keto compounds |
ITMI20090311A1 (en) * | 2009-03-04 | 2010-09-05 | Dipharma Francis Srl | PROCEDURE FOR THE PREPARATION OF KETONIC INTERMEDIATES |
ITMI20132023A1 (en) * | 2013-12-05 | 2015-06-06 | Dipharma Francis Srl | "METHOD OF PURIFICATION OF A KETONIC COMPOUND" |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2005532356A (en) * | 2002-06-10 | 2005-10-27 | テバ ファーマシューティカル インダストリーズ リミティド | Polymorph XVI of fexofenadine hydrochloride |
ITMI20131652A1 (en) | 2013-10-07 | 2015-04-08 | Dipharma Francis Srl | PROCEDURE FOR THE PURIFICATION OF DERIVATIVES OF 2-PHENYL-2-METHYL-PROPANOIC ACID |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4254130A (en) * | 1979-04-10 | 1981-03-03 | Richardson-Merrell Inc. | Piperidine derivatives |
US5654433A (en) * | 1993-01-26 | 1997-08-05 | Merrell Pharmaceuticals Inc. | Process for piperidine derivatives |
EP1178041A1 (en) * | 1994-05-18 | 2002-02-06 | Aventis Pharmaceuticals Inc. | Process for preparing anhydrous and hydrate forms of antihistaminic piperidine derivatives |
EP1260505A1 (en) * | 2001-05-17 | 2002-11-27 | Dinamite Dipharma S.p.A. | A process for the preparation of 4-[1-hydroxy-4-(4-(hydroxydiphenylmethyl)-1-piperidinyl)-butyl]-alpha, alpha-dimethylbenzeneacetic acid |
US20030166682A1 (en) * | 2000-07-28 | 2003-09-04 | Milla Federico Junquera | Processes for the production of fexofenadine |
-
2005
- 2005-05-31 EP EP05011646A patent/EP1616861A3/en not_active Withdrawn
- 2005-06-14 CA CA002510001A patent/CA2510001A1/en not_active Abandoned
- 2005-06-14 JP JP2005173319A patent/JP2006001931A/en active Pending
- 2005-06-14 US US11/151,406 patent/US20050277775A1/en not_active Abandoned
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4254130A (en) * | 1979-04-10 | 1981-03-03 | Richardson-Merrell Inc. | Piperidine derivatives |
US5654433A (en) * | 1993-01-26 | 1997-08-05 | Merrell Pharmaceuticals Inc. | Process for piperidine derivatives |
EP1178041A1 (en) * | 1994-05-18 | 2002-02-06 | Aventis Pharmaceuticals Inc. | Process for preparing anhydrous and hydrate forms of antihistaminic piperidine derivatives |
US20030166682A1 (en) * | 2000-07-28 | 2003-09-04 | Milla Federico Junquera | Processes for the production of fexofenadine |
EP1260505A1 (en) * | 2001-05-17 | 2002-11-27 | Dinamite Dipharma S.p.A. | A process for the preparation of 4-[1-hydroxy-4-(4-(hydroxydiphenylmethyl)-1-piperidinyl)-butyl]-alpha, alpha-dimethylbenzeneacetic acid |
Non-Patent Citations (1)
Title |
---|
KAWAI S H ET AL: "A FACILE SYNTHESIS OF AN OXIDANT PRODUCT OF TERFENADINE" JOURNAL OF ORGANIC CHEMISTRY, AMERICAN CHEMICAL SOCIETY. EASTON, US, vol. 59, 1994, pages 2620-2622, XP002064406 ISSN: 0022-3263 * |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1992615A1 (en) | 2007-05-16 | 2008-11-19 | Dipharma Francis S.r.l. | A process for the preparation of keto compounds |
US8236961B2 (en) | 2007-05-16 | 2012-08-07 | Dipharma Francis S.R.L. | Process for the preparation of keto compounds |
ITMI20090311A1 (en) * | 2009-03-04 | 2010-09-05 | Dipharma Francis Srl | PROCEDURE FOR THE PREPARATION OF KETONIC INTERMEDIATES |
ITMI20132023A1 (en) * | 2013-12-05 | 2015-06-06 | Dipharma Francis Srl | "METHOD OF PURIFICATION OF A KETONIC COMPOUND" |
Also Published As
Publication number | Publication date |
---|---|
US20050277775A1 (en) | 2005-12-15 |
EP1616861A3 (en) | 2006-02-08 |
JP2006001931A (en) | 2006-01-05 |
CA2510001A1 (en) | 2005-12-15 |
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